Major depressive disorder (MDD) is prevalent, debilitating, and costly both to individuals and society. One of the challenges with this heterogeneous syndrome is our inability to identify clinically and biologically distinct subsets of patients and so treatment assignment is fairly arbitrary. Omega-3 polyunsaturated fatty acids (n-3 PUFA) are a focus of treatment research for many medical and psychiatric disorders. Work from our previous R01 identified a homogeneous set of subjects with MDD who were particularly responsive to the n-3 PUFA eicosapentaenoic acid (EPA): subjects with MDD who had multiple biomarkers indicating high inflammation. The one clinical characteristic correlated with the presence of high inflammatory markers was obesity (BMI >30). In fact, 48% of our obese subjects with MDD (vs. 11% in our normal weight group) had baseline levels of high sensitivity C-Reactive Protein (hs-CRP) > 3 mg/l, the accepted cut-point for defining high inflammation. All of the obese subjects with high hs-CRP met criteria for high inflammation on multiple additional markers of inflammation. The overall goal of the UG3 phase of this proposal is to conduct a pilot placebo-controlled, dosefinding study of EPA (1 g/day vs 2 g/day vs 4 g/day) among obese (body mass index (BMI) ?30 and waist circumference >100 cm for men and > 93 cm for women) patients with major depressive disorder (MDD) who have high inflammatory status at baseline [levels of high sensitivity C-Reactive Protein (hs-CRP) ?3 mg/l. The primary aim of this proposal is to evaluate whether a dose-response relationship exists between dose of EPA and a decrease either in plasma IL-6 levels or in mitogen-stimulated PBMC TNF-? expression and secretion, when compared with placebo. Aim 2 of this proposal will evaluate whether EPA treatment produces a decrease in ratings of depression severity, when compared with placebo-treated subjects; and whether the changes in IL-6 or mitogen- stimulated PBMC TNF-? expression will mediate changes observed in ratings of depression. A go/no go decision rule will be utilized to drive the UH3 phase of this proposal. The UH3 phase will be a fully powered clinical efficacy study that will utilize the optimal dose of EPA identified in the UG3 phase to evaluate the efficacy of EPA against the symptoms of depression, and to modulate the identified biomarkers from the UG3 phase as objective markers of the mechanism of the antidepressant effect of the omega-3 fatty acid. Successful completion of this UG3/UH3 proposal will have significant public health consequences: (1) we will provide the first test of one potential mechanism responsible for the antidepressant effect of n-3 fatty acids; (2) we will identify a cohort of patients with MDD who are likely to respond to treatment with a relatively benign natural product; and (3) we will advance the concept of personalized medicine in the field of psychiatry.